Vascular reactivity in heart failure: Role of myosin light chain phosphatase

Congestive heart failure (CHF) is a clinical syndrome, which is the result of systolic or diastolic ventricular dysfunction. During CHF, vascular tone is regulated by the interplay of neurohormonal mechanisms and endothelial-dependent factors and is characterized by both central and peripheral vasoconstriction as well as a resistance to nitric oxide (NO)-mediated vasodilatation. At the molecular level, vascular tone depends on the level of regulatory myosin light chain phosphorylation, which is determined by the relative activities of myosin light chain kinase and myosin light chain phosphatase (MLCP). The MLCP is a trimeric enzyme with a catalytic, a 20-kDa and a myosin targeting (MYPT1) subunit. Alternative splicing of a 3′ exon produces leucine zipper positive and negative (LZ^+/-) MYPT1 isoforms. Expression of a LZ ^+/- MYPT1 has been suggested to be required for NO-mediated smooth muscle relaxation. Thus, we hypothesized that the resistance to NO-mediated vasodilatation in CHF could be attributable to a change in the relative expression of LZ^+/- MYPT1 isoforms. To test this hypothesis, left coronary artery ligation was used to induce CHF in rats, and both the dose response relationship of relaxation to 8-Br-cGMP in skinned smooth muscle and the relative expression of LZ^+/- MYPT1 isoforms were determined. In control animals, the expression of the LZ⁺ MYPT1 isoform predominated in both the aorta and iliac artery. In CHF rats, LVEF was reduced to 30±5% and there was a significant decrease in both the sensitivity to 8-Br-cGMP and expression of the LZ⁺ MYPT1 isoform. These results indicate that CHF is associated with a decrease in the relative expression of the LZ⁺ MYPT1 isoform and the sensitivity to 8-Br-cGMP-mediated smooth muscle relaxation. The data suggest that the resistance to NO-mediated relaxation observed during CHF lies at least in part at the level of the smooth muscle and is a consequence of the decrease in the expression of the LZ ⁺ MYPT1 isoform.